X-Message-Number: 32183
Date: Sun, 29 Nov 2009 10:44:51 -0800 (PST)
From:
Subject: cryoprotectant toxicity neutralization by quercetin I
[Quercetin eliminates DMSO induced toxicity, and greatly reduces glycerol
or ethanol induced damage. Quercetin also reduces cold storage-induced
renal injury, and possibly reduces ice crystal growth. However good
brain permeation would likely require liposome encapsulation. It is a
mystery why inexpensive quercetin does not see use in cryopreservation
solutions.]
Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3714-8.
Responses of human lens epithelial cells to quercetin and DMSO.
Cao XG, Li XX, Bao YZ, Xing NZ, Chen Y. Department of Ophthalmology, People's
Hospital of Peking University, Beijing, Peoples Republic of China.
PURPOSE: Oxidative stress is an initiating factor in the development of
maturity-onset cataract. Diet has a significant impact on cataract
development, and individual dietary components responsible for the
protective effect include flavonoids, of which quercetin is the most
important. The purpose of this study was to investigate the protective
effect of quercetin and its toxicity for human lens epithelial cells
(HLECs). METHODS: HLECs in culture were incubated for 48 hours with either
1% (vol/vol) dimethyl sulfoxide (DMSO) alone or with this concentration of
DMSO and between 0.1 and 100 microM of quercetin. Nonstimulated cells served
as control cultures. The viability of HLECs was measured by the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)
colorimetric assay. Gene expression was assessed with reverse
transcription-polymerase chain reaction (RT-PCR). Cellular apoptosis was
examined by in situ immunocytochemistry using terminal deoxynucleotidyl
transferase-mediated biotin-dUTP nicked labeling (TUNEL) and by flow
cytometry, using annexin V-FITC apoptosis detection. RESULTS: DMSO (1%
vol/vol) decreased cell viability, increased cellular apoptosis, and
upregulated Bax in these cells; 0.1 microM quercetin inhibited these effects
and protected HLECs from the toxicity of DMSO. Higher concentrations of
quercetin the viability of HLECs decreased. In a dose-dependent response to
quercetin, cellular apoptosis increased and the change correlated with
upregulation of Bax and decreased cell viability. CONCLUSIONS: Quercetin, at
a low concentration (0.1 microM), protects HLECs and reverses the toxic
effects of DMSO (1% vol/vol). However, at higher concentrations, quercetin
is toxic to HLECs with an LD(50) of 90.85 microM. Quercetin induced
apoptosis and upregulates apoptotic genes in HLECs in a dose-dependent
manner.
PMID: 17652743
Brain Res. 1998 Jun 1;794(2):304-8.
Dimethyl sulfoxide, but not acidosis-induced metallothionein mRNA expression in
neonatal rat primary astrocyte cultures is inhibited by the bioflavonoid,
quercetin.
Conklin DR, Tan KH, Aschner M. Department of Physiology and Pharmacology, Wake
Forest University School of Medicine, Winston-Salem, NC, USA.
Metallothionein (MT) mRNA levels were analyzed following exposure of
neonatal rat primary astrocyte cultures to physiologic pH (7.4), acidosis
(pH 6.5 and 6.0), and dimethyl sulfoxide (DMSO). Treatments were carried out
both in the presence and absence of the bioflavonoid, quercetin. Total RNA
was probed on northern blots with [alpha32P]dCTP-labeled synthetic cDNA
probes specific for rat MT isoform mRNAs. MT-I and MT-II mRNA levels in
astrocytes exposed to pH 6.5 or pH 6.0 were increased compared to controls
(pH 7.4). Treatment with DMSO in the presence and absence of acidosis, also
increased MT-I and MT-II mRNA levels compared to controls (pH 7.4). The
DMSO-induced increase in MT mRNA expression was reversed by treatment of
astrocytes with quercetin, such that MT-I and MT-II mRNA levels in DMSO plus
quercetin-treated astrocytes were indistinguishable from mRNA levels in
their respective controls at pH 7.4, pH 6.5, and pH 6.0. These findings
suggest that both acidosis and DMSO exposure are associated with increased
astrocytic MT synthesis at the mRNA level, and that quercetin, effectively
blocks MT mRNA induction by DMSO. Copyright 1998 Elsevier Science B. V. All
rights reserved.
PMID: 9622659
Pharmacology. 2005 Jan;73(1):49-56. Epub 2004 Sep 27.
Reversal of experimental myoglobinuric acute renal failure in rats by quercetin,
a bioflavonoid.
Chander V, Singh D, Chopra K. Division of Pharmacology, University Institute of
Pharmaceutical Sciences, Panjab University, Chandigarh, India.
The occurrence of acute renal failure (ARF) following rhabdomyolysis has
been put at between 10 and 40% of cases, and accounts for between 3 and 15%
of all cases of ARF. Reactive oxygen intermediates have been demonstrated to
play an etiological role in myoglobinuric renal failure. This study was
performed to explore the protective effect of quercetin, a bioflavonoid, in
an experimental model of myoglobinuric ARF in rats. Four groups of rats were
employed in this study: group 1 served as control, group 2 was given 50%
glycerol (8 ml/kg, i.m.), group 3 was given glycerol + quercetin (2 mg/kg,
i.p.), and group 4 was given glycerol + DMSO (the solvent for quercetin, 5
ml/kg, i.p.). Renal injury was assessed by measuring serum creatinine, blood
urea nitrogen, creatinine and urea clearance. The oxidative stress was
measured by renal malondialdehyde levels, reduced glutathione levels and by
enzymatic activity of catalase, glutathione reductase, and superoxide
dismutase. Glycerol administration resulted in a marked renal oxidative
stress, significantly deranged the renal functions as well as renal
cytoarchitecture. All these factors were significantly improved by quercetin
treatment. Because of its radical-scavenging and iron-chelating properties,
quercetin protected the kidney against the glycerol-induced oxidative
stress and resultant renal dysfunction. Based on these results, this study
confirms the role of oxidative stress and demonstrates the renoprotective
potential of quercetin in this rhabdomyolysis-mimicking model. 2005 S.
Karger AG, Basel.
PMID: 15452363
Am J Physiol Gastrointest Liver Physiol. 2009 Jun;296(6):G1318-23. Epub 2009 Mar
26.
The protective role of HO-1 and its generated products (CO, bilirubin, and Fe)
in ethanol-induced human hepatocyte damage.
Yao P, Hao L, Nussler N, Lehmann A, Song F, Zhao J, Neuhaus P, Liu L, Nussler A.
Universitatsmedizin Berlin, Charite, Campus Virchow, Department of General,
Visceral, and Transplantation Surgery, Berlin, Germany.
It has been reported that naturally occurring quercetin exerts
hepatoprotective effects through heme oxygenase-1 (HO-1) induction. However,
the precise mechanism of how ethanol-associated liver damage is
counteracted by quercetin-enhanced HO-1 metabolism still remains unclear. To
further decipher the protective role of quercetin on ethanol-induced liver
damage, we treated human hepatocytes with quercetin and various (end)
products of the HO-1 pathway. Our data clearly showed that quercetin
treatment attenuated ethanol-induced damage, whereas hemoglobin and zinc
protoporphyrin 9 (ZnPP) abolished such effects. Iron-II aggravated ethanol
toxicity and was only partially reduced by quercetin. In contrast, carbon
monoxide (CO) dose dependently inhibited ethanol-induced cytochrome P450 2E1
(CYP 2E1) activity and hepatotoxicity but had no influence on CYP 2E1
protein expression. Similarly, hemoglobin dramatically stimulated CYP 2E1
activity but not the protein expression in quercetin- and ethanol-cotreated
hepatocytes. ZnPP significantly promoted CYP 2E1 protein expression in the
presence and absence of CO treatment but inhibited ethanol-induced CYP 2E1
activation following CO incubation in quercetin- and ethanol-cotreated
hepatocytes. These results suggested that quercetin virtually attenuated
ethanol-derived oxidative damage via HO-1 induction. Heme degradation and CO
release may mediate the protective effects through inhibiting
ethanol-induced CYP 2E1 synthesis and enzymatic activity, respectively.
PMID: 19325051
World J Gastroenterol. 2008 May 28;14(20):3242-8.
Effects of quercetin on hyper-proliferation of gastric mucosal cells in rats
treated with chronic oral ethanol through the reactive oxygen species-nitric
oxide pathway.
Liu JL, Du J, Fan LL, Liu XY, Gu L, Ge YB. Department of Physiology, Nanjing
Medical University, Nanjing 210029, Jiangsu Province, China.
AIM: To investigate the effect of quercetin (3,3',4',5,7-pentahydroxy
flavone), a major flavonoid in human diet, on hyper-proliferation of gastric
mucosal cells in rats treated with chronic oral ethanol. METHODS: Forty
male Sprague-Dawley rats, weighing 200-250 g, were randomly divided into
control group (tap water ad libitum), ethanol treatment group (6 mL/L
ethanol), quercetin treatment group (intragastric gavage with 100 mg/kg of
quercetin per day), and ethanol plus quercetin treatment group (quercetin
and 6 mL/L ethanol). Expression levels of proliferating cell nuclear antigen
(PCNA) and Cyclin D1 were detected by Western blot to assay gastric mucosal
cell proliferation in rats. To demonstrate the influence of quercetin on
the production of extra-cellular reactive oxygen species/nitrogen species
(ROS/RNS) in rats, changes in levels of thiobarbituric acid reactive
substance (TBARS), protein carbonyl, nitrite and nitrate (NOx) and
nitrotyrosine (NT) were determined. The activity of inducible nitric oxide
synthase (NOS) including iNOS and nNOS was also detected by Western blot.
RESULTS: Compared to control animals, cell proliferation in the gastric
mucosa of animals subjected to ethanol treatment for 7 days was significant
increased (increased to 290% for PCNA density P < 0.05, increased to 150 for
Cyclin D1 density P < 0.05 and 21.6 +/- 0.8 vs 42.3 +/- 0.7 for PCNA
positive cells per view field), accompanied by an increase in ROS generation
(1.298 +/- 0.135 micromol vs 1.772 +/- 0.078 micromol for TBARS P < 0.05;
4.36 +/- 0.39 mmol vs 7.48 +/- 0.40 mmol for carbonyl contents P < 0.05) and
decrease in NO generation (11.334 +/- 0.467 micromol vs 7.978 +/- 0.334
micromol P < 0.01 for NOx; 8.986 +/- 1.351 micromol vs 6.854 +/- 0.460
micromol for nitrotyrosine P < 0.01) and nNOS activity (decreased to 43%
P<0.05). This function was abolished by the co-administration of quercetin.
CONCLUSION: The antioxidant action of quercetin relies, in part, on its
ability to stimulate nNOS and enhance production of NO that would interact
with endogenously produced reactive oxygen to inhibit hyper-proliferation of
gastric mucosal cells in rats treated with chronic oral ethanol.
PMID: 18506933
Biol Pharm Bull. 2003 Oct;26(10):1398-402.
Quercetin, a flavonoid antioxidant, prevents and protects against
ethanol-induced oxidative stress in mouse liver.
Molina MF, Sanchez-Reus I, Iglesias I, Benedi J. Department of Pharmacology,
Faculty of Pharmacy, UCM, Madrid, Spain.
This study evaluates whether quercetin (25, 50 and 75 mg/kg body weight)
treatment has a protective effect on the pro-oxidant-antioxidant state
following chronic ethanol treatment in mice. Pretreatment (quercetin 25, 50
and 75 mg/kg body weight for 15 d+co-treatment of ethanol 18%+quercetin for
15 d and ethanol 18% for the 15 d) increased the activities of superoxide
dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione
reductase (GR), and glutathione (GSH) in comparison to the ethanol group. No
significant differences from the ethanol group were observed in the group
after post-treatment (ethanol 18% for 30 d+quercetin 25, 50 and 75 mg/kg
body weight for 15 d) with quercetin. A significant increase in lipid
peroxidation (malondialdehyde, MDA) products was observed in liver tissue
after administration of ethanol, which was attenuated by pre- and
post-treatment with a high dose of quercetin. GSH levels increased and
oxidized glutathione (GSSG) levels decreased in groups of ethanol-exposed
mice that received quercetin for 15 d prior to ethanol exposure. In
conclusion, pre-treatment of quercetin may protect against ethanol-induced
oxidative stress by directly quenching lipid peroxides and indirectly by
enhancing the production of the endogenous antioxidant GSH. There was no
protective effect on post-treatment with quercetin.
PMID: 14519943
Arch Toxicol. 2005 Jan;79(1):25-30. Epub 2004 Nov 4.
Oxidation of ethanol to acetaldehyde and free radicals by rat testicular
microsomes.
Quintans LN, Castro GD, Castro JA. Centro de Investigaciones Toxicologicas
(CEITOX) - CITEFA/CONICET, J.B. de La Salle 4397, B1603ALO Villa Martelli,
Buenos Aires, Argentina.
A large number of epidemiological studies evidencing that excessive alcohol
consumption is associated with impaired testosterone production and
testicular atrophy are available in the literature. One hypothesis to
explain the deleterious action of alcohol involves the in situ
biotransformation to acetaldehyde, but it strongly suggests the need to
learn more about the enzymatic processes governing alcohol metabolism to
acetaldehyde in different cellular fractions since limited information is
available in the literature. In this article we report studies on the
metabolic conversion of alcohol to acetaldehyde and to 1-hydroxyethyl
radicals in rat testicular microsomal fractions. The oxidation of ethanol to
acetaldehyde in rat testes microsomal fraction was mostly of enzymatic
nature and strongly dependent on the presence of NADPH and oxygen. Several
compounds were able to significantly decrease the production of
acetaldehyde: SKF 525A; diethyldithiocarbamate; esculetin; gossypol;
curcumin; quercetin; dapsone; and diphenyleneiodonium. Microsomal
preparations in the presence of NADPH were also able to produce both
hydroxyl and 1-hydroxyethyl free radicals. Their generation was modulated by
the presence of diphenyleneiodonium, gossypol, and deferoxamine. Results
show that rat microsomal fractions are able to metabolize alcohol to
deleterious chemicals, such as acetaldehyde and free radicals, that may be
involved in ethanol toxic effects. Enzymes involved could include CYP2E1,
P450 reductase, and other enzymes having lipoxygenase- /peroxidase-like
behavior.
PMID: 15526191
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